No Significant Association between Radiation Therapy and Subsequent Malignancies in Patients with Li-Fraumeni Syndrome: A Multi-Institutional Hereditary Cancer Registry Study

Abstract

Li-Fraumeni Syndrome (LFS) is a rare cancer-predisposing disease caused by germline mutations in a potent tumor suppressor gene calledTP53. Accordingly, LFS patients carry a high lifetime risk of developing multiple primary cancers. Conventional wisdom and prior work have suggested that the risk of developing a subsequent malignancy is increased by the use of radiation therapy (RT) during primary or secondary cancer treatment. This risk, however, is not well characterized. Here we describe the risk of subsequent malignancy and cancer-related death in LFS patients after undergoing RT for a first or second primary cancer. We reviewed a cohort of patients in a multi-institution hereditary cancer registry with germline TP53 mutations. We assessed the rate of subsequent malignancy and death in patients who received RT (RT group) as part of their cancer treatment against those who did not (non-RT group). We further evaluated outcomes after RT with respect to p53 mutation type. Among 41 LFS patients (14 males and 28 females from 28 different families), 22 TP53mutations were present. 61% (25) and 7% (3) of patients had missense mutations in the DNA binding domain and tetramerization domain of p53, respectively, and 27% (11) had truncating mutations caused by nonsense (3), frameshift (1), splice site (2), or deletion (5) mutations. The median age of first cancer diagnosis was 22 years. 13 patients received RT with curative intent as part of their cancer treatment which included 3 for locally recurrent disease. The median time to follow up after RT was 5.0 years. 61% of patients in the RT group compared to 40% of patients in the non-RT group developed a subsequent malignancy (P=0.31). The median time to subsequent malignancy in the RT group and non-RT group was 3.2 years and 4.3 years respectively. Although 4 patients developed a subsequent malignancy within the radiation field, all were of the same initial histology and none of the cancers had features of an RT-induced secondary malignancy. To date, 8 deaths have occurred in the RT group (median age 36.5 years) and 2 deaths in the non-RT group (median age 30.5 years). The 5-year overall survival (OS) for the RT group was 54% compared to 95% in the non-RT group (P=0.033). Notably, there was no association between the type of p53 mutation and the rate of subsequent malignancy after RT. LFS patients who received RT for a primary cancer suffered from subsequent malignancies and death at a higher rate than those who did not receive RT. However, these results must be interpreted with caution as the majority of patients within the RT-treated group had more aggressive cancers with a higher risk of recurrence. We found that all 4 in-field malignancies in the RT-group likely represent locally recurrent disease and not RT-induced malignancies. Accordingly, the higher rate of mortality in the RT-group is likely a reflection of more aggressive cancer diagnoses and not their treatment.